Prothrombin levels are increased in the estrogen-treated immature rat uterus.
An estrogen-responsive uterine proenzyme of a proteinase in the immature rat uterus has been known for some time. Its mol wt is 77,000, its N-terminal amino acid sequence is the same as prothrombin's for 15 residues, it contains gamma-carboxyl glutamate residues, its biosynthesis is prevented by warfarin, it cross-reacts with antibodies to human and rat prothrombin, and it can be activated by human factor Xa or a uterine procoagulant. The products of activation, when separated on sodium dodecyl sulfate-gels, react with antibodies to human or rat prothrombin to give bands that have mol wt corresponding to those of the products of activation of prothrombin. These activation intermediates hydrolyze synthetic substrates specific for thrombin and have the same mol wt as the activation products of prothrombin. The proteinase generated in the activation has the following properties of thrombin: it is inhibited by hirudin and PheProArg-chloromethyl ketone, it has kinetic constants similar to those of thrombin with tripeptide p-nitroanilides as substrates, and it digests actin to give the same peptides as thrombin. We conclude that the uterine proenzyme is prothrombin. The time course of the prothrombin response to estrogen suggests that prothrombin enters the uterus as part of the transudation of plasma proteins that occurs after estrogen stimulation. A membrane-bound uterine procoagulant that activates uterine prothrombin also increases in response to estrogen stimulation. We propose that the simultaneous increase in these two activities results in a localized generation of thrombin, a well characterized mitogen in fibroblasts and epithelial cells. Our results suggest that thrombin may have a vital function as a mitogen in the early steps of the estrogen-stimulated hypertrophy and hyperplasia of the immature uterus.
Henrikson
K P
KP
Wadsworth Center for Laboratories and Research, New York State Health Department, Albany 12201-0509.
Jazin
E E
EE
Greenwood
J A
JA
Dickerman
H W
HW
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000991:Antithrombins / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015151:Immunoblotting; D008970:Molecular Weight; D011516:Prothrombin / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014599:Uterus / Q000254:growth & development / Q000378:metabolism*
D000590:Amino Acid Chloromethyl Ketones; D000991:Antithrombins; D004792:Enzyme Precursors; D004967:Estrogens; D011516:Prothrombin; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone; D002118:Calcium